Got chest pain? Then pop some aspirin and head to the ER. This was, in a nutshell, the conclusion of the Second International Study of Infarct Survival (ISIS-2). 1.5 million Americans suffer from a heart attack every year and many are treated in the ER with morphine, oxygen, nitrates, aspirin and beta-blockers. Some are taken to the cath lab. Part of this methodical management stems from the results of ISIS-2. Prior to ISIS-2, there was exactly one trial that examined the use of aspirin, an anti-platelet agent, acutely during a myocardial infarction (MI). (In that study, one dose of aspirin was given for a suspected MI, and mortality was assessed at one month. The single dose conferred no mortality benefit and the authors concluded that aspirin was not beneficial in the acute setting.) The focus on streptokinase in ISIS-2 was less groundbreaking as there were a number of other concurrent trials studying the use of thrombolytic therapy for MIs. Still, in conjunction with other randomized clinical trials (GISSI, ISAM, etc), they quickly established a time frame of 3 hours for thrombolytic therapy, giving rise to the phrase “time is muscle”. Today, with rapid triage at the ED and improved times to percutaneous coronary intervention (PCI), we know it as 90 minutes for “door to balloon”.
The methodology in the study was consistent throughout the trial. Eligibility was made straight forward to encourage participation in various countries and ultimately 17,187 patients were recruited for the study. Patients were randomized for both aspirin and streptokinase. This created 4 distinct groups: streptokinase infusion, aspirin 160mg, streptokinase + aspirin, or placebo infusion and tablets. Participating physicians were encouraged to continue all other aspects of patient care as they saw fit, though they were required to report the intention to use any anticoagulation in addition to the trial medications. At the time of publication, discharge information on 204 patients (1.1%) was not available. Otherwise follow-up was strong, with 97% follow-up at 5 weeks after discharge and a median follow-up of 15 months.
Both 5-week mortality and 24-month mortality were analyzed. Aspirin afforded a 23% reduction in the odds of death when given within 24 hours of the onset of chest pain and continued for a month. This translates into 25 deaths avoided per 1000 patients treated (NNT of 40) and 15 non-fatal cardiovascular events avoided. This effect was further enhanced if aspirin was given within 4 hours of pain; mortality benefits were less pronounced if given after 4 hours. When examining both fatal and non-fatal events in the years following a myocardial infarction, the number needed to treat is far less than 40. This survival benefit was independent of the survival gains witnessed with streptokinase therapy. The combination of thrombolytic and anti-platelet therapy, administered within 4 hours of onset of chest pain, lead to a reduction of 40-50% in odds of death.
The administration of aspirin in the setting of an acute MI can substantially alter the outcome. Moreover, the gains in survival over the first few weeks persist well into the future with smaller amounts of daily aspirin. These benefits, definitively established by ISIS-2, cannot be understated. Simply put, for the 1.5 million MIs that occur in the US every year, taking a drug that is already found in nearly all households can prevent tens of thousands of deaths.
ISIS-2 Collaborative Group. Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet. 1988. Aug 13;2(8607):349-60.
(for those at UTSW, I can e-mail you a photocopy of the article since it isn’t available online through the library)